In previous studies, we and others showed evidence for the aberrant re-expression of a number of cell cycle-related proteins in specific vulnerable neuronal populations in Alzheimer disease (AD). That a mitotic cell cycle-related mechanism may play an important role in disease pathogenesis is highlighted by the earlier occurrence of cell cycle proteins compared to abnormal tau in AD. Furthermore, that cell cycle proteins are representative of a true cell cycle, rather than being an epiphenomena of other processes, is evident from recent evidence showing that, in AD and other neurodegenerative diseases, there is a true mitotic alteration that leads to DNA replication. These findings led us to develop a novel hypothesis that neurodegeneration in AD, like cancer, is a disease of inappropriate cell cycle control. To delineate the importance of cell cycle re- entry in mature neurons, we have recently developed a bitransgenic mouse model that inducibly expresses SV40Tspecifically in forebrain neurons (CaMKII-SV40T). In our preliminary analysis of these CaMKII-SV40T mice, we found that SV40T expression drives neurons to re-enter the cell cycle and causes hyperphosphorylation of tau. The goal of this proposal is to further determine the importance of neuronal cell cycle re-entry using this CaMKII-SV40T mouse. At the conclusion of these studies, we hope to not only have advanced our understanding consequences of neuronal cell cycle re-entry, particularly as it applies to AD, but also suggest novel therapies that could be manipulated to either prevent initiation of degeneration or stimulate recovery of damaged neurons in neurodegenerative conditions. Aberrant cell cycle activation in neurons is now emerging as a key pathogenic mechanism of neurodegeneration in many neurodegenerative diseases such as Alzheimer disease. However, its exact role in disease pathogenesis is unclear primarily because of the absence of research models to study cell cycle re-entry in adult neurons in vivo. Therefore, the goal of the project is to delineate the importance of neuronal cell cycle re- entry using a novel transgenic mouse (CaMKII-SV40T) where cell cycle re-entry in forebrain neurons can be activated in an inducible manner. [unreadable] [unreadable]